Prediction of cardiotoxicity

Abstract

The likelihood that a compound will exhibit cardiotoxicity in an in vitro or in vivo assay predicted by the ability of the compound to inhibit at least one kinase from a selected group.

1 . A method for predicting the cardiotoxicity of a compound, said method comprising:
 a) providing a test compound;   b) determining the ability of the compound at a concentration of about 10 μM to inhibit the kinase activity in the model kinase group consisting of CSF1R, KIT, FYN, PDGFR beta, FGR, LCK, Ephrin Receptor B1, FRK, ABL1, PDGFR alpha, and HCK, wherein inhibition by over 80% of at least one of said kinases indicates a likelihood that said test compound will demonstrate cardiotoxicity.   
     
     
         2 . The method of  claim 1 , wherein inhibition by over 80% of at least five of said kinases in the model kinase group indicates a likelihood that said compound will demonstrate cardiotoxicity. 
     
     
         3 . The method of  claim 1 , wherein inhibition by over 80% of all eleven of said kinases in the model kinase group indicates a likelihood that said test compound will demonstrate cardiotoxicity. 
     
     
         4 . The method of  claim 1 , wherein step b) further comprises determining the ability of the compound at 10 μM to inhibit the kinase activity in the potential model kinase group consisting of ABL2, LYN, ZAK, Ephrin Receptor B2, YES1, MAP4K4, PKN1, BRAF, DDR2, MAP4K5, and STK24, wherein inhibition by over 80% of at least one of said kinases in the potential model kinase group indicates a likelihood that said test compound will demonstrate cardiotoxicity. 
     
     
         5 . The method of  claim 4 , wherein wherein inhibition by over 80% of at least five of said kinases in the model kinase group indicates a likelihood that said compound will demonstrate cardiotoxicity. 
     
     
         6 . The method of  claim 4 , wherein inhibition by over 80% of all eleven of said kinases in the model kinase group indicates a likelihood that said test compound will demonstrate cardiotoxicity. 
     
     
         7 . A method for screening compounds for potential cardiotoxicity, said method comprising:
 a) providing a plurality of test compounds;   b) determining the ability of each compound at 10 μM concentration to inhibit the kinase activity in the model kinase group consisting of CSF1R, KIT, FYN, PDGFR beta, FGR, LCK, Ephrin Receptor B1, FRK, ABL1, PDGFR alpha, and HCK, wherein inhibition by over 80% of at least one of said kinases indicates a likelihood that said test compound will demonstrate cardiotoxicity;   c) rejecting compounds that demonstrate a likelihood of cardiotoxicity.   
     
     
         8 . The method of  claim 7  wherein inhibition by over 80% of at least five of said kinases in the model kinase group indicates a likelihood that said compound will demonstrate cardiotoxicity. 
     
     
         9 . The method of  claim 7  wherein inhibition by over 80% of all eleven of said kinases in the model kinase group indicates a likelihood that said test compound will demonstrate cardiotoxicity. 
     
     
         10 . The method of  claim 1  or  claim 7 , wherein the ability of the compound to inhibit the kinase activity is determined by measuring the binding affinity of the compound for said kinases. 
     
     
         11 . A test substrate, comprising:
 A solid support; and   Immobilized on said solid support, the kinases CSF1R, KIT, FYN, PDGFR beta, FGR, LCK, Ephrin Receptor B1, FRK, ABL1, PDGFR alpha, and HCK.   
     
     
         12 . The test substrate of  claim 9 , further comprising:
 Immobilized on said solid support, the kinases ABL2, LYN, ZAK, Ephrin Receptor B2, YES1, MAP4K4, PKN1, BRAF, DDR2, MAP4K5, and STK24.